Reduced beta-cell compensation to the insulin resistance associated with obesity in members of caucasian familial type 2 diabetic kindreds.

Abstract

A b b re v i a t i o n s :A I R g l u c o s e , acute insulin response to glucose; DI, disposition index; FSIGT, frequently sampled intravenous glucose tolerance test; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; S I , insulin sensitivity index.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Reduced -Cell Compensation to the Insulin Resistance Associated Wi t h O b e s ity in Members of Caucasian Familial Type 2 Diabetic Kindre d s O R I G I N A L A R T I C L EO B J E C T I V E -Both obesity and a family history of diabetes reduce insulin sensitivity, but the impact of obesity on insulin secretion among individuals predisposed to diabetes is uncertain. We used a pedigree-based approach to test the hypothesis that -cell compensation to the insulin resistance associated with obesity is defective among individuals predisposed to diabetes by virtue of a strong family history of type 2 diabetes before the development of diabetes or glucose intolerance.RESEARCH DESIGN AND METHODS -A total of 126 members of 26 families ascertained for at least a sib pair with type 2 diabetes with onset before age 65 years underwent a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT). Family members included 26 individuals with impaired glucose tolerance and 100 individuals with no rmal glucose tolerance (NGT). The acute insulin response to glucose (AIR g l u c o s e ) was determ i n e d and insulin sensitivity (S I ) estimated by minimal model analysis of FSIGT data. The -cell compensation for insulin sensitivity was estimated from the disposition index (DI), calculated as the product of S I and AIR g l u c o s e . Obesity was measured by BMI. R E S U LT S -Among all individuals, BMI was a significant predictor of both S I and AIR g l u c o s e , as expected. However, BMI also significantly predicted DI (P = 0.002) after correcting for age, sex, family membership, and glucose tolerance status. The relationship of BMI and DI was confirm e d in 85 individuals with NGT who were aged 45 (P = 0.002) but not in 91 unrelated control individuals without a family history of diabetes. When normoglycemic individuals aged 45 were separated into three classes by BMI ( 27,(27)(28)(29)(30) 30), S I d e c reased pro g ressively and significantly with o b e s i t y, where as A I R g l u c o s e rose significantly from lean to most obese classes. In cont r a s t t o t h e e x p e c t a t i o n o f c o m p l e te -cell compensation with o b e s i t y, D I fell significantly (P = 0.004) among obese family members. This relationship was not observed in control subjects.C O N C L U S I O N S -Individuals with a genetic predisposition to diabetes show a re d u c e d -cell compensatory response to the reduced insulin sensitivity associated with obesity. We propose that this impaired compensation may be one manifestation of the underlying genetic defect in susceptible individuals. This finding helps explain the multiplicative ...

Reduced insulin secretion in offspring of African type 2 diabetic parents.

“…Total area under the glucose response curve was high in the offspring and, coupled with the normal fasting insulin concentrations, suggests an abnormality of insulin secretion rather than action. Individuals with a genetic predisposition to type 2 diabetes show a reduced ␤-cell compensatory response to reduced insulin sensitivity associated with obesity (17,21). Our findings remained unchanged after adjustment for BMI, and there was no evidence of increased hepatic insulin extraction, since the insulin-to-C-peptide ratio was normal, which might affect the fasting insulin concentrations.…”

Prevalence of type 2 diabetes among women with a previous history of gestational diabetes mellitus

“…However, the product of insulin sensitivity and the acute insulin response, an index of b-cell compensation in response to insulin sensitivity termed the disposition index (DI), is more familial than first-phase insulin secretion or insulin sensitivity alone [28]. The DI is significantly lower in subjects with a family history of T2DM [29][30][31][32] than in controls. These studies support the notion that individuals with a family history of T2DM have an underlying genetic defect that renders them susceptible to this disease.…”

Insulin sensitivity, insulin secretion and β-cell function during puberty in overweight Hispanic children with a family history of type 2 diabetes

“…AIRg reflects the first phase endogenous insulin secretion (within the first 10 min) in response to the glucose infusion, and DI (SI Â AIRg) provides an estimate of b-cell function. 21 Glucose was measured in duplicate using a Yellow Springs Instrument 2700 Analyzer (Yellow Springs Instrument, Yellow Springs, OH, USA) and a glucose oxidase kit. Insulin was assayed in duplicate using a specific human insulin enzyme-linked immunosorbent assay kit (Linco, St Charles, MO, USA).…”